DESCRIPTION: The hallmark of HIV infection is the progressive decline in CD4+ T cells in the peripheral blood and the eventual collapse of the immune system, despite an apparently small number of HJ\T-infected cells in this tissue. Despite intensive study, the mechanisms by which CD4+ cells are progressively lost are still unknown and hotly debated. However, the SIV/macaque model of HIV infection provides the opportunity to simultaneously examine the mechanisms of CD4+ T cell depletion and turnover in various tissue compartments, and at different stages of infection. Recent studies have demonstrated that rapid and profound depletion of CD4+ T cells occurs specifically within the intestine in the first few days of SIV infection, whereas minimal changes occur in peripheral lymphoid tissues at these time points. Additional studies demonstrated that this may be due to distinct phenotypic differences between CD4+ T cell subsets residing in mucosal and peripheral lymphoid tissues. The goals of the proposed studies are to determine how CD4+ T cells are lost throughout the course of SIV infection by simultaneously examining primary, peripheral, and mucosal lymphoid tissues at various stages of SlV infection and disease. The specific aims are to; (1) Define the mechanisms of CD4+ T cell loss in SIV infection; by examining the relative contributions of cytotoxic T cell-mediated killing, apoptosis, CD4 antigen down regulation, and direct viral lysis to the overall loss of CD4+ T cells in various immunologic tissues. This will be accomplished by determining the effects of CD8 depletion on the CD4 T cell loss, quantifying SlV-specific CTLs in tissues throughout infection, and by multivariate flow cytometric analysis techniques to assess apoptosis, lysis and CD4 antigen down regulation in cells derived from primary, mucosal, and systemic lymphoid tissues, and; (2) Examine the rates of T cell turnover in primary, mucosal and peripheral lymphoid tissues in SIV infection; by determining the rates of both CD4 and CD8+ T cell proliferation at various stages of SlY infection. This will be accomplished by comparing levels of Ki-67 expression and rates of BrdUrd incorporation in CD4+ and CD8+ T cell subsets derived from various immunologic tissues. These studies will provide valuable information regarding the mechanisms of CD4+ T cell loss and turnover in HIV/SIV infection, and may provide answers to many of the mysteries involved in the pathogenesis of HIV/SIY infection.